Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28

Daniela Di Bella, Federico Lazzaro, Alfredo Brusco, Massimo Plumari, Giorgio Battaglia, Annalisa Pastore, Adele Finardi, Claudia Cagnoli, Filippo Tempia, Marina Frontali, Liana Veneziano, Tiziana Sacco, Enrica Boda, Alessandro Brussino, Florian Bonn, Barbara Castellotti, Silvia Baratta, Caterina Mariotti, Cinzia Gellera, Valentina FracassoStefania Magri, Thomas Langer, Paolo Plevani, Stefano Di Donato, Marco Muzi-Falconi, Franco Taroni

Research output: Contribution to journalArticlepeer-review


Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.

Original languageEnglish
Pages (from-to)313-321
Number of pages9
JournalNature Genetics
Issue number4
Publication statusPublished - Apr 2010

ASJC Scopus subject areas

  • Genetics


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